Intracellular Iron Metabolism and Cellular Iron Homeostasis

2009 ◽  
pp. 223-269 ◽  
Keyword(s):  
Iron Metabolism ◽  
Iron Homeostasis ◽  
Intracellular Iron ◽  
Cellular Iron ◽  
Cellular Iron Homeostasis

Overexpression of mitochondrial ferritin causes cytosolic iron depletion and changes cellular iron homeostasis

Blood ◽  
2005 ◽  
Vol 105 (5) ◽  
pp. 2161-2167 ◽  
Author(s):  
Guangjun Nie ◽  
Alex D. Sheftel ◽  
Sangwon F. Kim ◽  
Prem Ponka
Keyword(s):  
Iron Homeostasis ◽  
Rna Binding ◽  
Binding Activity ◽  
Intracellular Iron ◽  
Free Radical Damage ◽  
Iron Regulatory Proteins ◽  
Cellular Iron ◽  
Cellular Iron Uptake ◽  
A Cell ◽  
Cellular Iron Homeostasis

AbstractCytosolic ferritin sequesters and stores iron and, consequently, protects cells against iron-mediated free radical damage. However, the function of the newly discovered mitochondrial ferritin (MtFt) is unknown. To examine the role of MtFt in cellular iron metabolism, we established a cell line that stably overexpresses mouse MtFt under the control of a tetracycline-responsive promoter. The overexpression of MtFt caused a dose-dependent iron deficiency in the cytosol that was revealed by increased RNA-binding activity of iron regulatory proteins (IRPs) along with an increase in transferrin receptor levels and decrease in cytosolic ferritin. Consequently, the induction of MtFt resulted in a dramatic increase in cellular iron uptake from transferrin, most of which was incorporated into MtFt. The induction of MtFt caused a shift of iron from cytosolic ferritin to MtFt. In addition, iron inserted into MtFt was less available for chelation than that in cytosolic ferritin and the expression of MtFt was associated with decreased mitochondrial and cytosolic aconitase activities, the latter being consistent with the increase in IRP-binding activity. In conclusion, our results indicate that overexpression of MtFt causes a dramatic change in intracellular iron homeostasis and that shunting iron to MtFt likely limits its availability for active iron proteins.

scholarly journals Direct Activation of Genes Involved in Intracellular Iron Use by the Yeast Iron-Responsive Transcription Factor Aft2 without Its Paralog Aft1

2005 ◽  
Vol 25 (15) ◽  
pp. 6760-6771 ◽  
Author(s):  
Maïté Courel ◽  
Sylvie Lallet ◽  
Jean-Michel Camadro ◽  
Pierre-Louis Blaiseau
Keyword(s):  
Iron Homeostasis ◽  
Regulatory Elements ◽  
Intracellular Iron ◽  
Transcription Analysis ◽  
Dna Microarray Data ◽  
Cellular Iron ◽  
Surface Iron ◽  
Transcription Activators ◽  
Responsive Element ◽  
Cellular Iron Homeostasis

ABSTRACT The yeast Saccharomyces cerevisiae contains a pair of paralogous iron-responsive transcription activators, Aft1 and Aft2. Aft1 activates the cell surface iron uptake systems in iron depletion, while the role of Aft2 remains poorly understood. This study compares the functions of Aft1 and Aft2 in regulating the transcription of genes involved in iron homeostasis, with reference to the presence/absence of the paralog. Cluster analysis of DNA microarray data identified the classes of genes regulated by Aft1 or Aft2, or both. Aft2 activates the transcription of genes involved in intracellular iron use in the absence of Aft1. Northern blot analyses, combined with chromatin immunoprecipitation experiments on selected genes from each class, demonstrated that Aft2 directly activates the genes SMF3 and MRS4 involved in mitochondrial and vacuolar iron homeostasis, while Aft1 does not. Computer analysis found different cis-regulatory elements for Aft1 and Aft2, and transcription analysis using variants of the FET3 promoter indicated that Aft1 is more specific for the canonical iron-responsive element TGCACCC than is Aft2. Finally, the absence of either Aft1 or Aft2 showed an iron-dependent increase in the amount of the remaining paralog. This may provide additional control of cellular iron homeostasis.

scholarly journals Crucial function of vertebrate glutaredoxin 3 (PICOT) in iron homeostasis and hemoglobin maturation

2013 ◽  
Vol 24 (12) ◽  
pp. 1895-1903 ◽  
Author(s):  
Petra Haunhorst ◽  
Eva-Maria Hanschmann ◽  
Lars Bräutigam ◽  
Oliver Stehling ◽  
Bastian Hoffmann ◽  
...  
Keyword(s):  
Iron Metabolism ◽  
Iron Homeostasis ◽  
Regulatory Protein ◽  
Iron Regulation ◽  
Iron Starvation ◽  
Intracellular Iron ◽  
Cellular Iron ◽  
Cellular Iron Uptake ◽  
S Proteins

The mechanisms by which eukaryotic cells handle and distribute the essential micronutrient iron within the cytosol and other cellular compartments are only beginning to emerge. The yeast monothiol multidomain glutaredoxins (Grx) 3 and 4 are essential for both transcriptional iron regulation and intracellular iron distribution. Despite the fact that the mechanisms of iron metabolism differ drastically in fungi and higher eukaryotes, the glutaredoxins are conserved, yet their precise function in vertebrates has remained elusive. Here we demonstrate a crucial role of the vertebrate-specific monothiol multidomain Grx3 (PICOT) in cellular iron homeostasis. During zebrafish embryonic development, depletion of Grx3 severely impairs the maturation of hemoglobin, the major iron-consuming process. Silencing of human Grx3 expression in HeLa cells decreases the activities of several cytosolic Fe/S proteins, for example, iron-regulatory protein 1, a major component of posttranscriptional iron regulation. As a consequence, Grx3-depleted cells show decreased levels of ferritin and increased levels of transferrin receptor, features characteristic of cellular iron starvation. Apparently, Grx3-deficient cells are unable to efficiently use iron, despite unimpaired cellular iron uptake. These data suggest an evolutionarily conserved role of cytosolic monothiol multidomain glutaredoxins in cellular iron metabolism pathways, including the biogenesis of Fe/S proteins and hemoglobin maturation.

Control of Iron Availability in Cancer by MicroRNAs

2020 ◽  
Vol 14 (02) ◽  
pp. 61-77
Author(s):  
Kamesh R. Babu ◽  
Lei Sun
Keyword(s):  
Iron Metabolism ◽  
Iron Homeostasis ◽  
Cancer Prognosis ◽  
Iron Availability ◽  
Cellular Functions ◽  
Cellular Iron ◽  
Expression Of Genes ◽  
Non Coding Rna ◽  
Essential Nutrient ◽  
Cellular Iron Homeostasis

Iron is an essential nutrient required for normal cellular functions, growth, and proliferation. Iron homeostasis is maintained at the cellular and systemic levels by strict regulation of genes involved in the process of iron uptake, storage, export, and surveillance of iron levels. Cellular iron homeostasis is dysregulated in cancer to sustain rapid growth and proliferation. Cellular iron levels are increased in cancer by manipulating the expression of genes involved in iron metabolism. Recent studies show that a class of small non-coding RNA known as microRNA (miRNA) play a major role in the control of iron metabolism. This review summarizes the significance of iron in cancer prognosis and how miRNAs regulate the expression of genes involved in iron metabolism to increase the cellular iron availability in cancer.

scholarly journals Cardiac ferroportin regulates cellular iron homeostasis and is important for cardiac function

2015 ◽  
Vol 112 (10) ◽  
pp. 3164-3169 ◽  
Author(s):  
Samira Lakhal-Littleton ◽  
Magda Wolna ◽  
Carolyn A. Carr ◽  
Jack J. J. Miller ◽  
Helen C. Christian ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Iron Homeostasis ◽  
Iron Status ◽  
Cell Types ◽  
Cardiac Complications ◽  
Iron Loading ◽  
Intracellular Iron ◽  
Cellular Iron ◽  
Assessment And Treatment ◽  
Cellular Iron Homeostasis

Iron is essential to the cell. Both iron deficiency and overload impinge negatively on cardiac health. Thus, effective iron homeostasis is important for cardiac function. Ferroportin (FPN), the only known mammalian iron-exporting protein, plays an essential role in iron homeostasis at the systemic level. It increases systemic iron availability by releasing iron from the cells of the duodenum, spleen, and liver, the sites of iron absorption, recycling, and storage respectively. However, FPN is also found in tissues with no known role in systemic iron handling, such as the heart, where its function remains unknown. To explore this function, we generated mice with a cardiomyocyte-specific deletion of Fpn. We show that these animals have severely impaired cardiac function, with a median survival of 22 wk, despite otherwise unaltered systemic iron status. We then compared their phenotype with that of ubiquitous hepcidin knockouts, a recognized model of the iron-loading disease hemochromatosis. The phenotype of the hepcidin knockouts was far milder, with normal survival up to 12 mo, despite far greater iron loading in the hearts. Histological examination demonstrated that, although cardiac iron accumulates within the cardiomyocytes of Fpn knockouts, it accumulates predominantly in other cell types in the hepcidin knockouts. We conclude, first, that cardiomyocyte FPN is essential for intracellular iron homeostasis and, second, that the site of deposition of iron within the heart determines the severity with which it affects cardiac function. Both findings have significant implications for the assessment and treatment of cardiac complications of iron dysregulation.

scholarly journals FPN1, Targeted By Mir-17-5p, Regulates Cellular Iron Homeostasis Via activating Nrf2/Mir-17-5p/FPN1 Axis in Preclinical Model of Multiple Myeloma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5616-5616
Author(s):  
Yuanyuan Kong ◽  
Shuaikang Chang ◽  
Liangning Hu ◽  
Gege Chen ◽  
Yi Tao ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cell Proliferation ◽  
Cell Growth ◽  
Iron Homeostasis ◽  
Intracellular Iron ◽  
Myeloma Cells ◽  
Cellular Iron ◽  
Public Datasets ◽  
Cellular Iron Homeostasis

Abstract Abstract Multiple myeloma (MM) is a hematologic malignancy with lytic bone lessions, including dysregulation of iron homeostasis. Ferroportin (FPN1), the only known cellular iron exporter, has been demonstrated to have a dysregulated expression and to be associated with poor clinical outcome. However, the detailed mechanism of FPN1 in iron transportion is not clear. Our current study showed that miR-17-5p was another new FPN1 microRNA target, which had a negative correlation with FPN1 expression level in MM. We also identified that nuclear factor erythroid 2-related factor 2 (Nrf2) induced the transcription of miR-17-5p, which in turn suppressed the protein level of FPN1. Moreover, chromatin immunopreciptation (ChIP) and luciferase reporter assay revealed that Nrf2 directly inhibited the transcription of FPN1. Here, we investigated the mechanism of unbalanced Nrf2/miR-17-5p/FPN1 axis and CRISPR-mediated knockout of FPN1 function involved in iron metabolism of MM. To investigate the potential role of miR-17-5p in MM, several public datasets were analyzed, and we identified that miR-17-5p was significantly overexpressed in the progression of MM. We next examined the functional effect on cell proliferation and apoptosis, ARP1 and OCI-MY5 cells were transiently transfected with miR-17-5p mimics or inhibitors. The experiment revealed that miR-17-5p promoted proliferation, cell cycle and apoptosis resistance both in vitro and in vivo. Besides, we explored whether FPN1 could rescue the effect on cells growth by overexpressing FPN1 in MM cells co-transfecting with miR-17-5p mimics or scramble. Our results showed that FPN1 restoration partially induced an inhibitory effect on myeloma cells, confirming that miR-17-5p accumulation favored cell growth and survival by targeting FPN1. Furthermore, to investigate the regulatory mechanism of FPN1 in iron transportion, several transcription factor targeting predication algorithms were exploited, and we revealed that the FPN1 and miR-17-5p common target gene Nrf2, was significantly relative overexpressed in myeloma. We also analyzed the MM patient public datasets, including paired samples and different stages of disease, and all showed Nrf2 overexpression in relapsed MM with poor prognosis. Luciferase activity analysis verified that FPN1 was significantly inhibited when co-transfected, including truncated bodies of FPN1 promotor sequence. Meanwhile, ChIP-PCR showed that there was an interaction between Nrf2 and FPN1. Additionally, the direct interactions of Nrf2 with the miR-17-5p promoter were also confirmed, suggesting that Nrf2 bound to the miR-17-5p promoter region, thus regulating the transcription of miR-17-5p. These data indicateed that Nrf2 activation could modulate FPN1 levels directly or through miR-17-5p. To more comprehensively evaluate FPN1 in regulating iron exportation in MM, we introduced single guide (sg) RNA targeting FPN1 into MM cells stably expressing Cas9. Of note, CRISPR-mediated FPN1 knockout promoted the growth and increased intracellular iron levels. In addition, to test the requirement of iron for the growth of myeloma, two sgFPN1 depleted MM cells were treated with iron supplement Fecl3, or the iron chelator deferoxamine (DFO). Fecl3 had significantly increased intracellular iron while the effect treated with DFO was opposite. Besides, MM cell proliferation was significantly inhibited by DFO treatment, further confirming the role of intracellular iron in MM cell growth. We also analyzed the mRNA levels of signature genes involved in maintaining cellular iron homeostasis and the level of reactive oxygen species (ROS) generation during the iron-deficient or iron-abundant state, and our results showed that these genes involved in iron acquisition or iron storage were differentially expressed and influenced intracellular iron availability and ROS levels. In conclusion, our data suggested that the miR-17-5p/FPN1 axis induced by Nrf2 regulated intracellular liable iron pool, thus providing surplus iron for metabolic processes like DNA synthesis, the proliferation and growth of myeloma cells. Understanding the mechanisms on iron metabolism is important to develop new therapeutic strategies for clinical application to the treatment of MM. Funding This study was supported by grants from the National Natural Science Foundation of China (Nos. 81570190; 81670194 and 81529001). Disclosures No relevant conflicts of interest to declare.

Cellular Iron Homeostasis and Therapeutic Implications of Iron Chelators in Cancer

2014 ◽  
Vol 15 (12) ◽  
pp. 1125-1140 ◽  
Author(s):  
Mohsin Raza ◽  
Sankalpa Chakraborty ◽  
Monjoy Choudhury ◽  
Prahlad Ghosh ◽  
Alo Nag
Keyword(s):  
Iron Homeostasis ◽  
Iron Chelators ◽  
Therapeutic Implications ◽  
Cellular Iron ◽  
Cellular Iron Homeostasis

scholarly journals IRONOMYCIN KILLS DIFFUSE LARGE B‐CELL LYMPHOMA CELLS BY TARGETING CELLULAR IRON HOMEOSTASIS

2021 ◽  
Vol 39 (S2) ◽  
Author(s):  
J. Devin ◽  
T. Cañeque ◽  
Y.‐L. Lin ◽  
L. Mondoulet ◽  
J.‐L. Veyrune ◽  
...  
Keyword(s):  
B Cell ◽  
Iron Homeostasis ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Lymphoma Cells ◽  
Cellular Iron ◽  
Large B Cell Lymphoma ◽  
Cellular Iron Homeostasis ◽  
Large B Cell
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